Cited by Biocompatible Synthesis of Macrocyclic Thiazole Peptides from Chiral α-Amino Nitriles

Non-symmetric stapling of native peptides DOI

Fa‐Jie Chen, Wanzhen Lin, Fen‐Er Chen

et al.

Nature Reviews Chemistry, Journal Year: 2024, Volume and Issue: 8(5), P. 304 - 318

Published: April 4, 2024

Language: Английский

Citations

Phage-encoded bismuth bicycles enable instant access to targeted bioactive peptides DOI

Sven Ullrich, Upamali Somathilake, Minghao Shang

et al.

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: June 27, 2024

Abstract Genetically encoded libraries play a crucial role in discovering structurally rigid, high-affinity macrocyclic peptide ligands for therapeutic applications. Bicyclic peptides with metal centres like bismuth were recently developed as new type of constrained notable affinity, stability and membrane permeability. This study represents the genetic encoding peptide-bismuth peptide-arsenic bicycles phage display. We introduce tripotassium dicitrate (gastrodenol) water-soluble bismuth(III) reagent library modification situ bicyclic preparation, eliminating need organic co-solvents. Additionally, we explore arsenic(III) an alternative thiophilic element that is used analogously to our previously introduced core. The these elements instantaneous entirely biocompatible, offering advantage over conventional alkylation-based methods. In pilot display screening campaign aimed at identifying biotin-binding protein streptavidin, demonstrate enrichment dissociation constants two orders magnitude lower than those their linear counterparts, underscoring impact structural constraint on binding affinity.

Language: Английский

Citations

Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets DOI

Kilian Colas, Daniel Bindl, Hiroaki Suga

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(21), P. 12213 - 12241

Published: Oct. 25, 2024

Technological advances and breakthrough developments in the pharmaceutical field are knocking at door of "undruggable" fortress with increasing insistence. Notably, 21st century has seen emergence macrocyclic compounds, among which cyclic peptides particular interest. This new class potential drug candidates occupies vast chemical space between classic small-molecule drugs larger protein-based therapeutics, such as antibodies. As research toward clinical targets that have long been considered inaccessible, well-suited to tackle these challenges a post-rule 5 landscape. Facilitating their discovery is an arsenal high-throughput screening methods exploit massive randomized libraries genetically encoded compounds. These techniques benefit from incorporation non-natural moieties, non- proteinogenic amino acids or stabilizing hydrocarbon staples. Exploiting features for strategic architectural design challenging protein–protein interactions, resisted efforts. Review summarizes basic principles recent main focuses on specific deployment targeting undruggable space. A focus placed development guidelines cyclization structural stabilization resulting success stories achieved against well-known inaccessible targets.

Language: Английский

Citations

Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines DOI

Isaac J. Knudson, Taylor L. Dover,

Diondra A. Dilworth

et al.

Published: June 10, 2024

Expanding the chemical and structural complexity of genetically encoded peptides remains a challenge in peptide therapeutics discovery. Here we report that linear with reactive β- or γ-keto amide at their N-termini can be synthesized ribosomally using vitro translation methods. We show carrying an N-terminal β-keto converted into diverse heterocyclic quinoline-peptide hybrids via Friedländer reactions variety 2-aminoarylcarbonyl co-substrates. Reactions appropriately substituted 2-aminobenzophenones generated stable biaryl atropisomeric axes. In vitro-translated both internal 2-aminoacetophenone motif undergo intramolecular macrocyclization embed quinoline pharmacophore directly within macrocyclic backbone. The introduction ketide building blocks materials post-translational derivatization carbonyl chemistry simultaneously expands diversity provides paradigm for programmed synthesis peptide-derived more closely resemble complex natural products.

Language: Английский

Citations

Peptide–Bismuth Tricycles: Maximizing Stability by Constraint DOI

Lani J. Davies, Pritha Ghosh,

Sauhta Siryer

et al.

Chemistry - A European Journal, Journal Year: 2025, Volume and Issue: 31(8)

Published: Jan. 13, 2025

Abstract Constrained peptides possess excellent properties for identifying lead compounds in drug discovery. While it has become increasingly straightforward to discover selective high‐affinity peptide ligands, especially through genetically encoded libraries, their stability and bioavailability remain significant challenges. By integrating macrocyclization chemistry with bismuth binding, we generated series of linear, cyclic, bicyclic, tricyclic identical sequences. Utilizing rigidify the structure allows a better comparison different constraint levels, reducing confounding effects interactions often seen hydrophobic stapling reagents. Our study facilitated identification peptide–bismuth tricycle that fully withstands cellular levels glutathione, acts as nanomolar protease inhibitor without being proteolytically digested by its target, is stable human plasma. Importantly, this multicyclic does not any non‐canonical amino acid modifications. Using oxime ligation, conjugated an analogue N‐terminus two nanobodies demonstrate potential applications targeted therapy.

Language: Английский

Citations

Computational design of Bax-inhibiting peptides DOI

Tom Vlaar,

Bernadette Mayer,

Lars van der Heide

et al.

Materials Advances, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Cyclic peptides targeting Bax were designed and evaluated via MD simulations. The bind with high affinity, potentially modulating its apoptotic function. This approach offers a foundation for peptide-based therapeutics.

Language: Английский

Citations

The Potential of Peptide-Based Inhibitors in Disrupting Protein–Protein Interactions for Targeted Cancer Therapy DOI

Ana Maria Sardinha Afonso,

Carlos Cavaleiro, Miguel A. R. B. Castanho

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3117 - 3117

Published: March 28, 2025

Protein-protein interactions (PPIs) form an intricate cellular network known as the interactome, which is essential for various processes, such gene regulation, signal transduction, and metabolic pathways. The dysregulation of this has been closely linked to disease states. In cancer, these aberrant PPIs, termed oncogenic PPIs (OncoPPIs), are involved in tumour formation proliferation. Therefore, inhibition OncoPPIs becomes a strategy targeted cancer therapy. Small molecule inhibitors have dominant PPI owing their small size ability cross cell membranes. However, peptide-based emerged compelling alternatives, offering distinct advantages over inhibitors. Peptides, with larger flexible backbones, can effectively engage broad interfaces PPIs. Their high specificity, lower toxicity, ease modification make them promising candidates Over past decade, significant advancements made developing This review discusses critical aspects targeting emphasizes significance therapy, explores using therapeutic agents. It also highlights recent progress peptide design aimed at overcoming limitations therapeutics, comprehensive overview current landscape potential treatment.

Language: Английский

Citations

Peptide Therapeutics: Current Status and Future Opportunity with Focus on Nose-to-Brain Delivery DOI

Eva‐Maria Jülke, Annette G. Beck‐Sickinger

Peptides, Journal Year: 2025, Volume and Issue: unknown, P. 171404 - 171404

Published: April 1, 2025

Language: Английский

Citations

Biocompatible Synthesis of Macrocyclic Thiazol(in)e Peptides DOI

Junming He, Christoph Nitsche

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(38)

Published: May 6, 2024

Macrocyclic peptides containing a thiazole or thiazoline in the backbone are considered privileged structures both natural compounds and drug discovery, owing to their enhanced bioactivity, stability, permeability. Here, we present biocompatible synthesis of macrocyclic from N-terminal cysteine C-terminal nitrile. While is incorporated during solid-phase peptide synthesis, nitrile introduced cleavage with aminoacetonitrile, utilizing cleavable benzotriazole linker. This method directly yields fully functionalized linear precursor. The cyclization reaction occurs buffer at physiological pH room temperature. resulting heterocycle remains stable but hydrolyzes under acidic conditions. such hydrolysis enables access complete amide backbone, mild oxidation leads peptide. conventional strategies involve metals, developed protocol simply relying on alkaline salt air. Therefore, offer rapid metal-free pathway peptides, featuring key step.

Language: Английский

Citations

Employing unnatural promiscuity of sortase to construct peptide macrocycle libraries for ligand discovery DOI

Yanni Zhang,

Xiao-Cui Wan,

Yang Tang

et al.

Chemical Science, Journal Year: 2024, Volume and Issue: 15(25), P. 9649 - 9656

Published: Jan. 1, 2024

We report a sortase-based macrocyclization strategy in which low-reactive electrophiles are introduced into the SrtA recognition sequence (LPXTG) to enable construction of phage-displayed peptide macrocycle libraries for ligand discovery.

Language: Английский

Citations